The retinoid X receptor (RXR), a member of the nuclear-receptor superfamily, is a common binding partner for a subgroup of other nuclear receptors. RXR is able to form heterodimers with a number of nuclear receptors, such as retinoid acid receptors, peroxisome proliferator-activated receptors (PPAR), Liver X receptors (LXR), and farnesoid X receptor (FXR), and is a pleiotropic regulator involved in many biological pathways. With the development of RXR-specific agonists, such as bexarotene, tremendous potential exists to benefit many critical therapeutic areas, including metabolic syndrome, dermatologic disease, neurodegenerative diseases and disorders, treatment of tumors, and cancer prevention (13, 14, 30).
Bexarotene (also called Targretin, LGD1069) is a selective modulator of retinoid X receptors (RXRs) approved for treating refractory advanced-stage cutaneous T-cell lymphoma (1, 2). A number of preclinical studies and phase I and II clinical trials have shown that bexarotene also exhibits promising antitumor or tumor prevention activity for breast cancer, renal cell carcinoma and lung cancer (3-8). Consequently, two large phase III trials (SPIRIT I and SPIRIT II) were conducted to evaluate the efficacy and safety of standard chemotherapy agents with or without bexarotene as a first-line therapy in treating advanced non small cell lung cancer. The results from both phase III trials, however, showed that the addition of bexarotene to chemotherapy did not improve overall survival in the intent-to-treat population, the primary efficacy endpoint (9, 10). A known side-effect of retinoid therapy is the elevation of serum lipids, and the majority of the bexarotene treated patients in the two SPIRIT trials developed hypertriglyceridemia, as expected. Further analysis revealed that 30-40% of the patients appeared to be more sensitive to bexarotene treatment and developed NCI grade 3 or higher hypertriglyceridemia. Survival analysis in this subgroup of patients in each of the two trials revealed significantly longer survival compared to the patients in the control arm and to patients with low-grade hypertriglyceridemia (9, 10). This intriguing correlation between survival and triglyceride level induced by bexarotene observed in both SPIRIT trials is illustrated in FIG. 1A. Similar correlations were also revealed by retrospective analysis in other bexarotene cancer trials (11). These findings prompted the search for biomarkers which can predict bexarotene sensitivity and identify a subgroup of non small cell lung cancer patients whose survival could be prolonged by bexarotene treatment.